Prostaglandin E2 (abbreviated as PGE2) has been known as a metabolite in the arachidonate cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractive activity, a pain-inducing effect, a promoting effect on peristaltic movement, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity and so on.
A recent study has proved existence of various PGE subtype receptors possessing a different physical role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3, and EP4 (Negishi M., et al., J. Lipid Mediators Cell Signaling, 12, 379–391 (1995)).
Among these, it is thought that EP4 subtype receptor relates to inhibition of TNF-α production and acceleration of IL-10 production. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of immunological diseases (autoimmune disease such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus, etc., and rejection after organ transplantation, etc.), asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis (acute nephritis, chronic nephritis), renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock and glaucoma, etc. It is also thought that EP4 subtype receptor relates to protecting of mucosa. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of ulcer of gastrointestinal tract such as gastric ulcer and duodenal ulcer, etc. and stomatitis. It is also thought that EP4 subtype receptor relates to hair growth function. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of hair-disadvantaged and alopecia. Furthermore, it is also thought that EP4 subtype receptor relates to maturation of cervix. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the promoter of (maturation of) cervix.
Furthermore, the compounds which can bind on EP4 subtype receptor also have an action of accelerating bone formation, so it is expected to be useful for the prevention and/or treatment of diseases associated with loss in bone mass, for example,
1) primary osteoporosis (e.g., primary osteoporosis followed by aging, postmenopausal primary osteoporosis, primary osteoporosis followed by ovariectomy, etc.),
2) secondary osteoporosis (e.g., glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis, immunosuppressive-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis followed by Cushing's syndrome, rheumatoid osteoporosis, etc.),3) bone diseases such as bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss (alveolar bone loss, mandibular bone loss, childhood idiopathic bone loss, etc.), osteonecrosis, etc. Besides treatment of the above diseases, the present invention also includes a pharmaceutical composition for accelerating bone formation after bone operation (e.g., bone formation after fractures, bone formation after bone grafting, bone formation after operation of artificial joint, bone formation after spinal fusion and bone formation after the other operation for bone regeneration, etc.), or promoting treatment thereof, or alternative treatment for bone grafting.
It is also thought that EP4 subtype receptor relates to induction of physiological sleeping and suppression of blood platelet aggregation, so the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of sleep disorder and thrombosis.
The compounds which can bind on EP4 subtype receptor selectively do not have inducing pain which may be caused by EP, and uterine contraction which may be caused by EP3, so they are thought to be agents having no effect on the above actions.
As the EP4 agonistic compound, reported is the compound represented by formula (Ia) (cf. WO03/009872):

wherein  is a single bond or a double bond,
R19a and R20a are each independently, a hydrogen atom, C1–10 alkyl or a halogen atom,
Ta is oxygen or sulfur,
Xa is —CH2—, —O— or —S—,
Aa is A1a or A2a,
A1a is C2–8 straight-chain alkylene optionally substituted with 1–2 of C1–4 alkyl, C2–8 straight-chain alkenylene optionally substituted with 1–2 of C1–4 alkyl or C2–8 straight-chain alkynylene optionally substituted with 1–2 of C1–4 alkyl,
A2a is -G1a-G2a-G3a-,
G1a is C1–4 straight-chain alkylene optionally substituted with 1–2 of C1–4 alkyl, C2–4 straight-chain alkenylene optionally substituted with 1–2 of C1–4 alkyl or C2–4 straight-chain alkynylene optionally substituted with 1–2 of C1–4 alkyl,
G2a is —Ya—, -(ring1a)-, —Ya-(ring1a)-, -(ring1a)-Ya— or —Ya-(C1–4 alkylene)-(ring1a)-,
Ya is —S—, —SO—, —SO2—, —O— or —NR1a—,
R1a is a hydrogen atom, C1–10 alkyl or C2–10 acyl,
G3a is a bond, C1–4 straight-chain alkylene optionally substituted with 1–2 of C1–4 alkyl, C2–4 straight-chain alkenylene optionally substituted with 1–2 of C1–4 alkyl or C2–4 straight-chain alkynylene optionally substituted with 1–2 of C1–4 alkyl,
Da is D1a or D2a,
D1a is —COOH, —COOR2a, tetrazol-5-yl or CONR3aSO2R4a,
R2a is C1–10 alkyl, phenyl, C1–10 alkyl substituted with phenyl or biphenyl,
R3a is a hydrogen atom or C1–10 alkyl,
R4a is C1–10 alkyl or phenyl,
D2a is (1) —CH2OH, (2) —CH2OR5a, (3) hydroxy, (4) —OR5a, (5) formyl, (6) —CONR6aR7a, (7) —CONR6aSO2R8a, (8) —CO—(NH-amino acid residue-CO)m—OH, (9) —O—(CO— amino acid residue —NH)m—H, (10) —COOR9a, (11) —OCO—R10a, (12) —COO—Z1a—Zza—Z3a, or (13)

R5a is C1–10 alkyl,
R6a and R7a are each independently, a hydrogen atom or C1–10 alkyl,
R8a is C1–10 alkyl substituted with phenyl,
R9a is (1) C1–10 alkyl substituted with biphenyl optionally substituted with 1–3 of C1–10 alkyl, C1–10 alkoxy or a halogen atom or (2) biphenyl substituted with 1–3 of C1–10 alkyl, C1–10 alkoxy or a halogen atom,
R10a is phenyl or C1–10 alkyl,
m is 1 or 2,
Z1a is C1–15 alkylene, C2–15 alkenylene or C2–15 alkynylene,
Z2a is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR11a—, (5) —NR12aCO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO2—, (10) —NR13a—, (11) —NR14aCONR15a—, (12) —NR16aCOO—, (13) —OCONR17a— or (14) —OCOO—,
Z3a is (1) a hydrogen atom, (2) C1–15 alkyl, (3) C2–15 alkenyl, (4) C2–15 alkynyl, (5) ring2a or (6) C1–10 alkyl substituted with C1–10 alkoxy, C1–10 alkylthio, C1–10 alkyl-NR18a — or ring2a,
R11a, R12a, R13a, R14a, R15a, R16a, R17a and R18a are each independently, a hydrogen atom or C1–15 alkyl, R11a and Z3a may be taken together with the nitrogen atom to which they are attached to form 5- to 7-membered saturated monoheterocyclic ring, and said heterocyclic ring may contain other one hetero atom selected from oxygen, nitrogen and sulfur atom,
Ea is E1a or E2a,
E1a is C3–7 cycloalkyl or ring3a,
E2a is C3–7 cycloalkyl, ring4a or ring5a,
ring1a and ring5a are optionally substituted with 1–3 of R21a and/or R22a, ring3a is optionally substituted with 1–2 R21a,
C3–7 cycloalkyl represented by E2a is substituted with one of R21a or R22a, and optionally substituted with another 1–2 of R21a and/or R22a,
ring4a is substituted with one of R22a, optionally substituted with another 1–2 of R21a and/or R22a, and optionally substituted with a heterocyclic ring formed by R11a, Z3a and the nitrogen to which Z3a is attached or ring2a may be substituted with R23a,
R21a is C1–10 alkyl, C1–10 alkoxy, a halogen atom, nitro, C1–10 alkyl substituted with 1–3 of halogen atom(s) or phenyl,
R22a is (1) C2–10 alkenyl, (2) C2–10 alkynyl, (3) C1–10 alkylthio, (4) hydroxy, (5) —NR24aR25a, (6) C1–10 alkyl substituted with C1–10 alkoxy, (7) C1–10 alkyl substituted with C1–10 alkoxy substituted with 1–3 of halogen atom(s), (8) C1–10 alkyl substituted with —NR24aR25a, (9) ring6a, (10) —O-ring7a, (11) C1–10 alkyl substituted with ring7a, (12) C2–10 alkenyl substituted with ring7a, (13) C2–10 alkynyl substituted with ring7a, (14) C1–10 alkoxy substituted with ring7a, (15) C1–10 alkyl substituted with —O—ring7a, (16) —COOR26a or (17) C1–10 alkoxy substituted with 1–3 of halogen atom(s),
R24a, R25a and R26a are each independently, a hydrogen atom or C1–10 alkyl,
R23a is (1) C1–15 alkyl, (2) C2–15 alkenyl, (3) C2–15 alkynyl or (4) C1–10 alkyl substituted with C1–10 alkoxy, C1–10 alkylthio or C1–10 alkyl-NR27a-,
R27a is a hydrogen atom or C1–10 alkyl,
ring1a, ring2a, ring5a, ring6a and ring7a are (1) C3–15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or (2) 3- to 15-membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated,
ring3a and ring4a are thienyl, phenyl or furyl,
ring6a and ring7a may be substituted with 1–3 of R28a,
R28a is (1) C1–10 alkyl, (2) C2–10 alkenyl, (3) C2–10 alkynyl, (4) C1–10 alkoxy, (5) C1–10 alkyl substituted with C1–10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1–10 alkyl substituted with 1–3 of halogen atom(s) or (9) C1–10 alkyl substituted with C1–10 alkoxy substituted with 1–3 of halogen atom(s), and
wherein (1) when Ta is an oxygen atom, Xa is CH2—, Aa is A1a, and Da is D1a, then Ea is E2a,
(2) ring5a is not C3–7 cycloalkyl, phenyl, thienyl nor furyl,
(3) ring6a is phenyl, then phenyl have at least one R28a. The present invention is the selective invention in the WO03/009872 and the compounds in the present invention are included within the compound represented by formula (Ia).
In addition, the specification of U.S. Pat. No. 4,177,346 discloses the compound represented by formula (A)

wherein QA is selected from the group consisting of —COOR3A, tetrazol-5-yl and —CONHR4A;
AA is a single bond or a cis-double bond;
BA is a single bond or a trans-double bond;
UA is

R2A is selected from the group consisting of α-thienyl, phenyl, phenoxy, mono-substituted phenyl and mono-substituted phenoxy, and said substituent is selected from the group consisting of chlorine, fluorine, phenyl, methoxy, trifluoromethyl and C1–3 alkyl;
R3A is selected from the group consisting of hydrogen, C1–5 alkyl, phenyl and p-biphenyl;
R4A is selected from the group consisting of —COR5A and —SO2R5A;
R5A is selected from the group consisting of phenyl and C1–5 alkyl, and
a C5 epimer thereof, the salt of alkali metal and alkaline earth metals and ammonium salt of the compound which have carboxylate or tetrazol-5-yl.
And in the specification of JP-A-2001-181210, it is disclosed that the selective EP4 receptor agonist represented by above-mentioned formula (A) is useful for the treatment of osteoporosis.
And the specification of United Kingdom Patent No. 1,553,595 discloses the pyrrolidone derivatives represented by formula (B)

wherein R1B is a straight- or branched-chain, saturated or unsaturated, aliphatic hydrocarbon radical having up to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical having 3 to 7 carbon atoms, which radicals may be unsubstituted or substituted with one or more of the following: e) a cycloalkyl group of 3 to 7 carbon atoms, f) a phenyl, thienyl or furyl group which may carry one or two substituents selected from optionally halogenated alkyl group of 1 to 3 carbon atoms, halogen atoms and alkoxy group of 1 to 4 carbon atoms,
R2B is a straight- or branched-chain, saturated or unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms, or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and
nB is the integer 2, 3 or 4, and
a free acid, and the physiologically acceptable e.g. metal or amine, a salt thereof.
In the specifications of United Kingdom Patent No. 1,569,982, and United Kingdom Patent No. 1,583,163, the compound close to the compound represented by formula (B) is disclosed.
Further, the specification of U.S. Pat. No. 4,320,136 discloses the compound represented by formula (C)

wherein AC is —CH═CH— (cis or trans), —C≡C— or —CH2CH2—;
RC is hydrogen, C1–C12 n-alkyl, branched alkyl or cycloalkyl, etc.;
R1C is hydrogen, methyl or ethyl;
R2C is phenyl or mono- or di-substituted phenyl, said substituent is selected from the group consisting of, fluorine, chlorine, methyl, methoxy, nitro or trifuloromethyl;
when R2C is phenyl or substituted phenyl, nC is 0–2, the definitions of the symbols are excerpt.
Further, in the specification of WO02/042268 it was disclosed that the compound is EP4 receptor subtype agonist.